TUMOR CELL SYNTHESIS AND SECRETION OF PEPTIDE HORMONES

这项研究项目的目的是阐明在肿瘤中 内分泌和非内分泌来源的细胞及其正常 前体细胞通过其合成的分子事件， 多肽激素的储存和分泌受到调节。它 与转录、处理和结构有关 编码多肽和翻译的mRNAs， 翻译后加工、分泌和结构 多肽产品本身。它主要针对ACTH 和其他前阿片黑素皮质素(POMC)多肽。因为 脑下垂体瘤外分泌的POMC多肽 降钙素(CT)、精氨酸加压素 (AVP)和胃泌素释放肽(GRP)，因为 促肾上腺皮质激素释放激素(CRH)可能参与了 调节异位和在位POMC多肽分泌 可能是异位分泌的，肿瘤分泌的这些 多肽激素也将被研究。关于中国石油天然气集团公司 库欣综合征犬POMC多肽分泌的调节 疾病，一种罕见的人类疾病的常见动物模型，将 才能完成。DMS 79 POMC基因的结构分析 人小细胞肺癌细胞将通过以下方式阐明 的序列测定和/或S1核酸酶或核糖核酸酶作图 它不同寻常的5‘延伸。根本的问题是 肿瘤以异位方式或仅仅是 不恰当的答案将通过测量免疫反应性 正常大鼠和正常大鼠的POMC多肽和可杂交的POMC mRNA 人类组织，以及负责合成它们的细胞将是 免疫细胞化学和原位信使核糖核酸鉴定 组织切片杂交研究。成人叙利亚金色 一种全身性致癌物质二乙基亚硝胺对仓鼠 (DEN)，将进行研究以确定是否 由神经上皮体(NEB)组成的神经内分泌细胞 支气管上皮，当刺激到增生和 最终由DEN产生肿瘤，只会产生不适当的 他们的正常产品的数量，CT，或开始生产 异位POMC多肽，AVP或GRP，三种最常见的 肺癌产生的常见多肽。结果将会是 提供强有力的证据支持或反对荷尔蒙去抑制 正常细胞或正常来源不表达的基因。规管 正常大鼠肾上腺髓质细胞和PC12分泌POMC 大鼠肾上腺嗜铬细胞瘤细胞将在 分散细胞灌注柱系统。两种激动剂和 拮抗剂及其细胞内信号转导途径 将会被探索。灌流系统还将用于测试 假设对糖皮质激素的相对耐药性 人脑下垂体分泌POMC的负反馈 引起库欣病的微腺瘤仅仅是一种功能 手机号码。这些研究的结果将提供新的见解 关于多肽激素合成和分泌现象的探讨 通过肿瘤细胞。

The objective of this research project is to elucidate in tumor cells of endocrine and nonendocrine origin and in their normal precursor cells the molecular events by which the synthesis, storage, and secretion of polypeptide hormones are regulated. It is concerned with the transcription, processing, and structure of the mRNAs encoding the peptides and the translation, posttranslational processing, secretion, and structure of the peptide products themselves. It is directed primarily at ACTH and the other proopiomelanocortin (POMC) peptides. Because nonpituitary tumor secretion of POMC peptides is often associated with that of calcitonin (CT), arginine vasopressin (AVP), and gastrin-releasing peptide (GRP) and because corticotropin-releasing hormone (CRH) may be involved in regulating ectopic as well as eutopic POMC peptide secretion and may be ectopically secreted itself, tumor secretion of these polypeptide hormones will also be investigated. Studies on the regulation of POMC peptide secretion in the dog with Cushing's disease, a common animal model of a rare human condition, will be completed. The structure of the POMC mRNA from DMS 79 human small cell lung carcinoma cell will be elucidated by sequence determination and/or S1 nuclease or RNase mapping of its unusual 5' extension. The fundamental question whether tumors secrete these hormones ectopically or merely inappropriately will be answered by measuring immunoreactive POMC peptides and Hybridizable POMC mRNA in normal rat and human tissues, and the cells responsible for their synthesis will be identified by immunocytochemical and in situ mRNA hybridization studies on tissue sections. Adult Syrian golden hamsters to which a systemic carcinogen, diethylnitrosamine (DEN), is administered will be studied to determine if the neuroendocrine cells comprising neuroepithelial bodies (NEBs) in bronchial epithelium, when stimulated to hyperplasia and eventually neoplasia by DEN, merely produce inappropriate quantities of their normal product, CT, or begin to produce ectopically POMC peptides, AVP or GRP, three of the most common peptides produced by lung cancers. The results will provide strong evidence for or against derepression of hormonal genes not expressed by the normal cell or origin. Regulation of POMC secretion in normal rat adrenal medullary cells and PC12 rat adrenal pheochromocytoma cells will be examined in a dispersed cell perifusion column system. Both agonists and antagonists and their intracellular signal transduction pathways will be explored. The perfusion system will also be used to test the hypothesis that the relative resistance to glucocorticoid negative feedback in POMC-secreting human pituitary microadenomas causing Cushing's disease is simply a function of cell number. The results of these studies will provide new insights into the phenomenon of peptide hormone synthesis and secretion by tumor cells.